H2 receptor antagonists are a well known class of drugs used in the management of gastrointestinal disorders. H2 antagonists competitively inhibit the interaction of histamine with H2 receptors. Although H2 receptors are present in numerous tissues, including vascular and bronchial smooth muscle, they appear to have a minimal role in modulating physiological functions other than gastric secretion.
H2 receptor antagonists inhibit gastric acid secretion elicited by histamine and other H2 receptor agonists in a dose-dependent, competitive manner. The H2 receptor antagonists also inhibit acid secretion elicited by gastrin and, to a lesser extent, by muscarinic agonists. H2 receptor antagonists inhibit basal (fasting) and nocturnal acid secretion and that stimulated by food, sham feeding, fundic distention, and various pharmacological agents. The H2 receptor antagonists reduce both the volume of gastric juice secreted and its hydrogen ion (H+) concentration. Despite their good antisecretory properties, H2 receptor antagonists are not unanimously recognized as gastroprotective agents. In addition, there is a high relapse rate associated with treating gastrointestinal disorders with H2 receptor antagonists as they do not eliminate Helicobacter pylori (Campylobacter pylori), the bacteria responsible for peptic ulcer disease, gastric lymphoma and adenocarcinoma.
A variety of adverse reactions have been ascribed to H2 receptor antagonists, such as cimetidine and ranitidine, reflecting, in part, the very large number of patients who have been treated with these drugs. The incidence of adverse reactions is low, and the adverse reactions are generally minor. The low incidence is attributable in part to the limited function of H2 receptors in organs other than the stomach and to the poor penetration of these agents across the blood-brain barrier.
The most common side effects of H2 receptor antagonists, such as cimetidine, are headache, dizziness, nausea, myalgia, skin rashes, and itching. The incidence of symptoms related to the central nervous system (CNS) appears to be higher in the elderly and in patients with impaired renal function. Loss of libido, impotence and gynecomastia are sometimes observed in patients who receive long-term therapy with high doses of H2 receptor antagonists, such as cimetidine.
Sorba et al, Arzneim-Forsch Drug Res., 47(II):849–854 (1997), the disclosure of which is incorporated by reference herein in its entirety, have developed a drug that combines a H2 receptor antagonist with a nitric oxide (NO)-donor furoxan moiety. This drug is reported to retain weaker H2 receptor antagonist activity relative to the parent drug but shows a NO-dependent gastroprotective effect.
U.S. Pat. No. 5,403,830, the disclosure of which is incorporated by reference herein in its entirety, describes pharmaceutical compositions and methods of treating gastrointestinal disorders by administering bismuth-containing agents in conjunction with a H2 receptor antagonist. U.S. Pat. Nos. 5,403,830, and 5,407,688, and Ivnov et al, J. Pharm. Pharmacol., 48:297–301 (1996) and Marazova et al, J. Pharm. Pharmacol., 49:791–795 (1997), the disclosures of each of which are incorporated by reference herein in their entirety, describe treating or preventing gastrointestinal disorders by administering bismuth containing agents. U.S. Pat. Nos. 4,705,683, 4,900,741, 5,112,850 and 5,656,652, the disclosures of which are incorporated by reference herein in their entirety, describe administering H2 receptor antagonists with polyacrylates, antimuscarinic agents, trapencine and antacids, respectively. U.S. Pat. No. 5,656,652, the disclosure of which is incorporated by reference herein in its entirety, describes the use of H2 antagonists and antacids for the treatment of gastrointestinal disorders.
The administration of NSAIDs, such as indomethacin or ibuprofen, with H2 receptor antagonists, such as cimetidine, is described in U.S. Pat. Nos. 5,037,815 and 4,279,906 and in WO 94/07541, the disclosure of each of which is incorporated by reference herein in its entirety. U.S. Pat. Nos. 5,102,902, 5,541,212 and 5,578,597, the disclosures of each of which are incorporated by reference herein in their entirety, disclose the use of H2 receptor antagonists for treating multiple sclerosis and retrovirus infections.
There is a need in the art for H2 receptor antagonist compounds that have gastroprotective properties, decrease the recurrence of ulcers, facilitate ulcer healing and that can be used at low dosages. The invention is directed to these, as well as other, important ends.